Abstract

In order to investigate the reason why phenylpropanoic acid derivative (KCL), a potent, human peroxisome proliferator-activated receptor (PPAR) α-selective agonist, shows this selectivity, we analyzed the binding modes of KCL and a related compound to the ligand-binding domain of human PPARα and rat PPARα by means of computer-aided molecular modeling. We concluded that the characteristic specificity of KCL is due to a specific hydrophobic contact between the hydrophobic tail part (the 4-trifluoromethyl group) and the key amino acid Ile272 located on the helix three region of the human PPARα ligand binding domain. We propose a possible binding mode of KCL with the ligand-binding domain of human PPARα. This binding model should offer important insights for further structural design of subtype-selective PPARα agonists for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.

abstract = "In order to investigate the reason why phenylpropanoic acid derivative (KCL), a potent, human peroxisome proliferator-activated receptor (PPAR) α-selective agonist, shows this selectivity, we analyzed the binding modes of KCL and a related compound to the ligand-binding domain of human PPARα and rat PPARα by means of computer-aided molecular modeling. We concluded that the characteristic specificity of KCL is due to a specific hydrophobic contact between the hydrophobic tail part (the 4-trifluoromethyl group) and the key amino acid Ile272 located on the helix three region of the human PPARα ligand binding domain. We propose a possible binding mode of KCL with the ligand-binding domain of human PPARα. This binding model should offer important insights for further structural design of subtype-selective PPARα agonists for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.",

N2 - In order to investigate the reason why phenylpropanoic acid derivative (KCL), a potent, human peroxisome proliferator-activated receptor (PPAR) α-selective agonist, shows this selectivity, we analyzed the binding modes of KCL and a related compound to the ligand-binding domain of human PPARα and rat PPARα by means of computer-aided molecular modeling. We concluded that the characteristic specificity of KCL is due to a specific hydrophobic contact between the hydrophobic tail part (the 4-trifluoromethyl group) and the key amino acid Ile272 located on the helix three region of the human PPARα ligand binding domain. We propose a possible binding mode of KCL with the ligand-binding domain of human PPARα. This binding model should offer important insights for further structural design of subtype-selective PPARα agonists for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.

AB - In order to investigate the reason why phenylpropanoic acid derivative (KCL), a potent, human peroxisome proliferator-activated receptor (PPAR) α-selective agonist, shows this selectivity, we analyzed the binding modes of KCL and a related compound to the ligand-binding domain of human PPARα and rat PPARα by means of computer-aided molecular modeling. We concluded that the characteristic specificity of KCL is due to a specific hydrophobic contact between the hydrophobic tail part (the 4-trifluoromethyl group) and the key amino acid Ile272 located on the helix three region of the human PPARα ligand binding domain. We propose a possible binding mode of KCL with the ligand-binding domain of human PPARα. This binding model should offer important insights for further structural design of subtype-selective PPARα agonists for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.